Title: Type I collagen signaling in lung injury and fibrosis Abstract/Project Summary Progressive fibrosis is a complication of many chronic diseases and collectively, organ fibrosis is the leading cause of death in the US. Although many therapeutic strategies have dramatically attenuated fibrosis in animal models translating these findings into successful therapies for IPF has proven disappointing with several negative clinical trials and two new therapies only modestly slowing the progression of disease. Some have suggested the need for multi-modality therapies targeting different parts of the pro-fibrotic pathway. The current paradigm is that injury initiates a dynamic repair process that ultimately leads to fibrillar collagen deposition and scar formation. Progressive fibrosis is characterized by activation of self-amplifying feed-forward/positive feedback signaling pathways leading to excessive scarring. However, the ubiquity of the scar formation process after diverse injuries in nearly every tissue suggests that scarring may also be protective in limiting ongoing cellular and tissue damage and may be necessary to resolve the initial injury. Attempt at limiting collagen deposition may lead to persistence of the initial inciting stimuli. A more complete understanding into the linked mechanisms involved in the balance between progressive fibrosis and resolution of focal injurious stimuli is necessary. While matrix signaling during fibrosis has been studied, collagen I itself is often regarded as an end product of fibrosis but we have found that collagen I is also a critical mediator of progressive fibrosis. We have found that alveolar epithelial cell (AEC) apoptosis is a necessary and sufficient initiator of fibrosis and that a rigid collagen I matrix blunts the AEC apoptotic response to TGF?. In vivo, we found that collagen I expression is induced early after injury and collagen I-deficient mice have sustained lung injury and greater death. Collagen I signaling also enhances fibroblast recruitment and activation. Collagen can initiate signaling through specific integrins as well as a family of receptor tyrosine kinsases, the discoidin domain receptors (DDR). Our preliminary data support important and non-redundant roles for both ?2?1 integrin and DDR2 in regulation of this injury/fibrosis cycle. Thus, type I collagen is likely important in determining whether the response to injury is limited scar formation versus progressive fibrosis and potentially establishes a dilemma in which failure of fibrosis in the context of continued TGF?-induced AEC apoptosis could lead to greater foci of injury and suboptimal inhibition of profibrotic pathways. Our central hypothesis is type I collagen signaling promotes both propagation of fibrosis and inhibition of AEC apoptosis but these processes are regulated by distinct pathways. We will pursue studies aimed at understanding the mechanism of collagen I and its receptors in regulation of AEC apoptosis and fibroblast activation using reagents currently available in our lab including, primary murine and human diseased AECs and fibroblasts, decellularized lung matrix from normal human and IPF lungs as well as lungs from injured transgenic mice, coupled with in vivo experiments using novel transgenic mice.